Abstract
T lymphocytes have an essential role in adaptive immunity and rely on the activation of integrin lymphocyte function-associated antigen-1 (LFA-1) to mediate cell arrest and migration. In cancer, malignant cells modify the immune microenvironment to block effective host antitumor responses. We show for the first time that CD4 and CD8 T cells from patients with chronic lymphocytic leukemia (CLL) exhibit globally impaired LFA-1-mediated migration and that this defect is mediated by direct tumor cell contact. We show that following the coculture of previously healthy T cells with CLL cells, subsequent LFA-1 engagement leads to altered Rho GTPase activation signaling by downregulating RhoA and Rac1, while upregulating Cdc42. Of clinical relevance, repair of this T-cell defect was demonstrated using the immunomodulatory drug lenalidomide, which completely rescued adhesion and motility function by restoring normal Rho GTPase activation signaling. Our report identifies a novel cancer immune evasion mechanism whereby tumor cells induce Rho GTPase signaling defects in T cells that prevent appropriate LFA-1 activation and motility. We believe these findings identify important biomarkers and highlight the clinical utility of immunotherapy to rescue normal T-cell function in CLLs that are likely to have relevance in other cancers.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing
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Antineoplastic Agents / pharmacology
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Cell Movement / drug effects
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Cell Movement / immunology
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Coculture Techniques
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Humans
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Immunologic Factors / pharmacology
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Lenalidomide
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Leukemia, Lymphocytic, Chronic, B-Cell / drug therapy*
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Leukemia, Lymphocytic, Chronic, B-Cell / metabolism
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Leukemia, Lymphocytic, Chronic, B-Cell / pathology
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Lymphocyte Function-Associated Antigen-1 / metabolism*
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Peptide Hydrolases / metabolism
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Primary Cell Culture
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Signal Transduction / drug effects*
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Signal Transduction / immunology
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T-Lymphocytes / cytology
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T-Lymphocytes / drug effects*
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T-Lymphocytes / metabolism
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Thalidomide / analogs & derivatives*
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Thalidomide / pharmacology
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Tumor Cells, Cultured
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Ubiquitin-Protein Ligases
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cdc42 GTP-Binding Protein / metabolism
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rac1 GTP-Binding Protein / metabolism
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rho GTP-Binding Proteins / metabolism*
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rhoA GTP-Binding Protein / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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Antineoplastic Agents
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CRBN protein, human
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Immunologic Factors
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Lymphocyte Function-Associated Antigen-1
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RAC1 protein, human
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RHOA protein, human
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Thalidomide
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Ubiquitin-Protein Ligases
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Peptide Hydrolases
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cdc42 GTP-Binding Protein
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rac1 GTP-Binding Protein
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rho GTP-Binding Proteins
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rhoA GTP-Binding Protein
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Lenalidomide